Summary

• Canagliflozin can cause intravascular volume contraction, which may sometimes manifest as symptomatic hypotension or acute transient changes in creatinine. There have been postmarketing reports of acute kidney injury, which are likely related to volume depletion, some requiring hospitalizations and dialysis, in patients with type 2 diabetes mellitus (T2DM) receiving sodium-glucose co-transporter 2 inhibitors, including canagliflozin. Patients with impaired renal function (estimated glomerular filtration rate [eGFR] less than 60 mL/min/1.73 m²), elderly patients, or patients on loop diuretics may be at increased risk for volume depletion or hypotension. Before initiating canagliflozinin patients with one or more of these characteristics, assess and correct volume status. Monitor for signs and symptoms of volume depletion after initiating therapy.¹
• Canagliflozin results in osmotic diuresis, which may lead to reductions in intravascular volume. In clinical studies, treatment with canagliflozinwas associated with a dose-dependent increase in the incidence of volume depletion-related adverse reactions (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration). An increased incidence was observed in patients on the 300-mg dose. The three factors associated with the largest increase in volume depletion-related adverse reactions were the use of loop diuretics, moderate renal impairment (eGFR 30 to less than 60 mL/min/1.73 m²) and age 75 years and older.¹
• In the pooled, broad dataset involving 8 active- and placebo-controlled studies^2-9, the incidence of volume depletion-related adverse events (AEs) in patients concomitantly taking angiotensin-converting enzyme inhibitors (ACEIs) and/or angiotensin receptor blockers (ARBs) was reported in 3.5% of patients in the pooled INVOKANAgroup vs 1.7% of patients in the placebo group.¹⁰
• Weir et al (2014)¹¹ conducted an analysis of the effect of INVOKANA on blood pressure, osmotic diuresis, and intravascular volume reduction-related AEs using pooled data from 4 placebo-controlled, phase 3 studies^2,4,5,9 in patients with T2DM (N=2313). Of the 1268 patients on ACEI/ARB therapy at baseline, 94.2% remained on ACEIs/ARBs throughout the 26-week, double-blind periods. In the overall population, the incidence of intravascular volume reduction-related AEs (eg, orthostatic hypotension and postural dizziness) was 1.2%, 1.3%, and 1.1%, in the INVOKANA100 mg, 300 mg, and placebo groups, respectively.

CLINICAL STUDIES

Pooled, Broad Dataset of Phase 3 Studies

In the pooled, broad dataset (referred to as Dataset 3 [DS3]) involving 8 active- and placebo-controlled studies^2-9, the proportion of patients with volume depletion-related AEs (eg, hypotension, postural dizziness, orthostatic hypotension, syncope, and dehydration) was stratified by ACEIs/ARBs usage and is presented in Table: Patients with Volume Depletion-Related AEs by Baseline ACEI/ARB Usage in Eight Pooled Studies Representing Broader Population (DS3).

LITERATURE SEARCH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) pertaining to this topic was conducted on 11 November 2024.